This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal is to determine if in utero hematopoietic stem cell transplantation can be improved by co-transplantation of facilitating cells (mesenchymal stem cells and alloreactive natural killer cells). We hypothesize that the use of these cells will improve the competitiveness of donor stem cells and ultimately increase the level of chimerism that is achieved after in utero hematopoietic transplantation. Theoretically, in utero transplantation of hematopoietic stem cells should treat and cure many heritable disorders of the lymphohematopoietic system. Target diseases potentially include hemoglobinopathies, immune deficiencies, and leukodystophies. Most of these disorders exert their deleterious effects prior to birth making the rationale for in utero treatment imperative. The feasibility of in utero therapy is supported by a variety of natural occurring human and animal chimeras that demonstrate high levels of stable mixed chimerism. While donor stem cells have a competitive advantage in fetuses with severe combined immune deficiency successes, other experimental models and human clinical studies have not been as encouraging, and the levels of chimerism achieved were insufficient to successfully treat human fetal disease. Although the fetus is an ideal candidate for therapy it is clear that significant immunologic barriers exist that prevent clinically relevant levels of chimerism from being achieved. The present studies are designed to study the effects facilitating cells that modulate the fetal immune and hematopoietic systems on fetal engraftment, chimerism and risk of in utero graft versus host disease. If our hypotheses are correct, then in utero treatment for hematopoietic and immune disorders may become both safer and successful.